Pappa2 deletion in mice affects male but not female fertility

Abstract

BackgroundRecent studies have found associations between the gene encoding pregnancy associated plasma protein-A2 (PAPP-A2), a protease of insulin-like growth factor binding protein -5 (IGFBP-5), and measures of female reproductive performance in cattle. The purpose of the present study was to test the effects of Pappa2 deletion on reproduction in mice.FindingsWe measured the fertility and offspring growth of Pappa2 deletion females, and also performed reciprocal matings (i.e., deletion males mated to control females) to control for the effects of offspring genotype. Ovarian and testicular IGFBP-5 levels were measured by Western blotting. As expected, deletion of Pappa2 increased ovarian IGFBP-5 levels. However, Pappa2 deletion in females had no effect on the interval between pairing and the birth of the first litter, the interval between the births of the first and second litters, or litter size. Offspring weight was lower in the offspring of Pappa2 deletion females, but effects of similar magnitude were observed in the offspring of Pappa2 deletion males, suggesting that the effects were due to heterozygosity for the deletion in the offspring. Pappa2 deletion in males had no effect on litter size or the interval between pairing and the birth of the first litter. However, the interval between the births of the first and second litters was significantly longer in deletion males.ConclusionsPappa2 deletion had no effect on female reproductive performance. In contrast, Pappa2 deletion had subtle effects on male fertility, although the underlying mechanism remains to be elucidated.

Short stature with low insulin‐like growth factor 1 availability due to pregnancy‐associated plasma protein A2 deficiency in a Saudi family

“…The question regarding male fertility might be raised later as fertility is affected in PAPP-A2 deficient male mice but not females. 6 All cases reported to date have high total IGF1, IGFBP3, IGFALS, and stimulated GH levels, very low free IGF1 and very low or undetectable levels of PAPP-A2 3 ; however, the cases reported here did not have elevated IGF2 or IGFBP5. Fasting hyperinsulinism and impaired fasting glucose is reported in some pateints.…”

“…Thus, it is possible that pubertal delay is more common in males than in female PAPP‐A2 deficient patients. The question regarding male fertility might be raised later as fertility is affected in PAPP‐A2 deficient male mice but not females 6 …”

Insulin-Like Growth Factor Binding Proteins and IGFBP Proteases: A Dynamic System Regulating the Ovarian Folliculogenesis

“…Homozygous loss-of-function mutations in PAPP-A2 result in a novel syndrome of growth retardation with markedly elevated circulating IGF-I and IGF-II, but a decrease of bioactivity due to an increase in serum concentrations of IGFBP-3 and -5 sequestrating IGFs ( 93 ). In Pappa2 KO mice, ovarian IGFBP-5 expression increases, but Pappa2 deletion does not affect female reproduction ( 95 ). This phenotype does not mimic the complex phenotype of Igfbp-5 overexpressing transgenic mice showing reduced female fertility ( 96 ).…”

Pregnancy-Associated Plasma Protein (PAPP)-A2 in Physiology and Disease

“…Increased circulating levels of Igfbp5, recently confirmed in 2-month-old Pappa2 KO mice, were not influenced by gestation and recovery after lactation [ 71 ], with these variations also continuing to be observed in the plasma of older mice with a mean age of 7 months [ 69 ]. However, at 7 months of age, no effect of Pappa2 deletion was observed on mRNA levels of Igfbp3 or Igfbp5 in the liver or kidney, but Igfbp5 protein levels were increased in ovaries of female Pappa2 KO mice [ 72 ]. In contrast, osteoblast-specific deletion of Pappa2 did not alter circulating levels of Igfbp5 in mice at 18–19 days of age [ 65 ], suggesting a local Pappa2-Igfbp5 mechanism for Igf1 function in bone physiology not yet addressed.…”